Effectiveness of Risk Minimization Measures for Fentanyl Buccal Tablet (FENTORA) in Canada: A Mixed-Methods Evaluation Using Surveys, Medical Chart Records and Web Surveillance.

BACKGROUND: Fentanyl buccal tablet (FBT), a potent opioid, was approved in Canada in 2013 for breakthrough pain in opioid-tolerant adult cancer patients. Additional risk minimization measures (aRMMs), consisting of communications to patients and healthcare providers (HCPs), were implemented from November 2014 through September 2015. OBJECTIVES: The aim of this study was to assess the effectiveness of FBT aRMMs as measured by prescriber knowledge, understanding, and behavior regarding key safety concerns (off-label use, use in non-opioid-tolerant patients, misuse/abuse/diversion, and drug-drug interaction) and to evaluate illicit FBT use. METHODS: The study included three components: (1) a knowledge and understanding (KAU) survey of FBT prescribers conducted in two waves: November 2016-February 2017 and April-September 2018; (2) a retrospective prescription study of medical records of patients treated with FBT by a subgroup of prescribers from the KAU survey; and (3) Web surveillance of illicit FBT use in Canada using the search term FENTORA (May 2014-September 2018). The aRMMs were considered effective if the lower bound of the 95% confidence interval indicated that at least 65% of respondents met or partly met the knowledge objective for each key safety concern. RESULTS: KAU survey: Of 46 eligible HCPs, 97.8% met or partly met the knowledge objective on use in breakthrough pain cancer patients, 97.8% on use in opioid-tolerant patients, 89.1% on dose and titration, 100% on abuse/addiction, and 58.7% on drug-drug interaction. Retrospective prescription study: Of 22 FBT-treated patients identified from 14 HCPs, 45.5% had cancer, 50.0% recorded a breakthrough pain indication, and 36.4% reported opioid tolerance; however, only 13.6% of patients were prescribed FBT according to the approved indication. Web surveillance: Of 932 FBT posts in Canada, only 40 (4.3%) mentioned illicit use. CONCLUSIONS: The aRMMs as measured by the prescriber KAU were effective for most key safety messages; however, not all key messages of the aRMMs were stringently followed in routine practice.

Comparative efficacy and safety of estradiol transdermal preparations for the treatment of vasomotor symptoms in postmenopausal women: an indirect comparison meta-analysis.

OBJECTIVE: Divigel and Estrogel are estradiol gels for the treatment of postmenopausal women with moderate to severe vasomotor symptoms. They differ with respect to several factors including estradiol concentration and surface application, and cannot be compared solely on the basis of their estradiol dose. No randomized clinical trials have compared them head to head, but both have been compared with placebo. Therefore, the objective of this study was to conduct a systematic review and network meta-analysis of the two estradiol gels. METHODS: We performed a comprehensive systematic literature review. One publication reporting on one Divigel trial, three publications reporting on two Estrogel trials, and five publications reporting on other estradiol transdermal preparations were identified. Efficacy outcomes were change from baseline in daily hot flush frequency and change from baseline in daily hot flush severity. Safety outcomes were frequency of treatment-related adverse events (AEs) and frequency of treatment-emergent AEs leading to discontinuation. Bayesian indirect treatment comparison meta-analysis of trial-level data was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research, Academy of Managed Care Pharmacy, National Pharmaceutical Council (ISPOR-AMCP-NPC) Good Practice Questionnaire. All outcomes were compared with respect to doses of the considered preparations. RESULTS: For hot flush frequency, Divigel 0.25 mg was similar to Divigel 0.5 mg and to Estrogel 0.75 mg, and was statistically significantly superior to Estrogel 1.5 mg. The largest effect was observed with Divigel 1.0 mg (mean difference of 3.91 hot flushes/wk vs placebo), and was statistically significantly superior to all other interventions. The 1.5 mg Estrogel dose was associated with the smallest estimate of efficacy. For hot flush severity, Divigel 0.25 mg was similar to the efficacy of Divigel 0.5 mg, and for 0.25 mg and 0.5 mg of other estradiol gels, but was statistically inferior to Divigel 1.0 mg, Estrogel 0.75 mg, Estrogel 1.5 mg, and the 1.0 and 1.5 mg doses of all other estradiol gels. The estimated efficacy of Divigel 0.5 mg was similar to that of Estrogel 0.75 mg, Estrogel 1.5 mg, and the 0.25 and 0.5 mg doses of other transdermal estradiol preparations. Risks of treatment-related AEs for Divigel 0.25 mg, Divigel 0.5 mg, Estrogel 0.75 mg, and Estrogel 1.5 mg were similar and all were of a slightly higher risk than placebo. Among these, Divigel 1.0 mg, Estrogel 1.5 mg, and other gels 0.5 mg were statistically significantly less safe than placebo. However, for treatment-emergent AEs leading to discontinuation, none of the gels were associated with statistically significantly higher relative risks compared with placebo. In this study, statistically significant refers to the 95% credible intervals used in the Bayesian Network Analysis. CONCLUSIONS: Using network meta-analysis for indirect treatment comparison, we have shown that the efficacy of Divigel 0.25 mg, as measured by reduced hot flush frequency and severity, was similar to that of Divigel 0.5 mg and of Estrogel 0.75 and 1.5 mg. Overall, our analysis showed that Divigel 1.0 mg provided the best efficacy profile, but that this treatment was also associated with a higher risk of AEs. The network meta-analysis also showed that treatment with Estrogel 1.5 mg was associated with the smallest estimate of reduction in frequency of hot flushes.

Good efficiency of intrauterine insemination programme for serodiscordant couples with HIV-1 infected male partner: a retrospective comparative study.

OBJECTIVE: Assisted reproduction techniques can minimize the risk of HIV female contamination when the male partner is HIV-infected. The aim of this study was to investigate the efficiency of sperm washing and intrauterine insemination (IUI) in these couples. STUDY DESIGN: Retrospective comparative study. Eighty-four HIV-1 serodicordant couples underwent 294 IUI. The control group was composed of 90 couples (320 IUI cycles) with donor sperm. Spermatozoa from HIV-1 infected male partner were prepared and tested for HIV-1 according to sperm washing method. Spermatozoa from HIV-1 and donor male were frozen before IUI. IUI were performed after ovarian stimulation. Main outcomes measures were pregnancy rate per cycle and baby take-home rate per couples. RESULTS: Although the pregnancy rate and baby take-home rate were higher in IUI with sperm washing than in IUI using donor sperm (18.0 versus 14.7 and 52.4 versus 41.1, respectively), the differences were not statistically significant. In serodiscordant couples, blood estradiol levels under ovarian stimulation and total motile sperm inseminated were a determining factor in achieving pregnancy. No female HIV-1 contamination occurred. CONCLUSION: This study demonstrates that sperm washing and IUI are highly effective in enabling serodiscordant couples with an HIV-1 infected male partner to have a child.

High risk of temporary alteration of semen parameters after recent acute febrile illness.

OBJECTIVE: To report parameters in semen samples and sperm deoxyribonucleic acid integrity in a fertile volunteer presenting a 2-day fever of 39 degrees -40 degrees C. DESIGN: Case report. SETTING: University-affiliated teaching hospital. INTERVENTION(S): None. PATIENT(S): Semen samples from a fertile volunteer of proven fertility were obtained and analyzed before the febrile illness episode and at days 15, 37, 58, 79, and >180 after the fever. MAIN OUTCOME MEASURE(S): Semen parameters (total sperm count, motility a+b, and vitality), sperm protamination state, measured by sperm chromatin structure assay (SCSA) and apoptotic activities, measured by terminal uridine nick-end labeling (TUNEL) assay. RESULTS: Total sperm count significantly decreased at days 15, 37, and 58 after the fever and returned to normal by day 79 after the fever. The percentage of motility significantly decreased at days 15 and 37 after the fever and returned to normal by day 58. Vitality score also showed a slight, although not statistically significant, decrease after the fever. The DNA fragmentation index (DFI, a SCSA parameter), which defines abnormal chromatin structure, significantly increased by 24% and 36% at days 15 and 37 after the fever, respectively, and decreased to 15% and 8% when reaching days 58 and 79 after the fever. High DNA stainability (HDS, a SCSA parameter) also significantly increased at day 37 after the fever. On the other hand, sperm DNA fragmentation, as measured by TUNEL assay, increased up to 23% by day 15 after the fever but this was not statistically significant. CONCLUSION(S): This report demonstrates that a febrile episode can have marked effects on semen parameters and sperm DNA integrity. These results are particularly important for the counseling of infertile couples and in relation to assisted reproductive techniques (ART).

Decreased semen volume and spermatozoa motility in HIV-1-infected patients under antiretroviral treatment.

Inconsistent results have been reported for the semen quality in HIV-infected men, due to the biases inherent in some studies. The objective of the present study was to investigate the semen parameters in HIV-1-infected patients and to compare their sperm characteristics with those of a control group of fertile, noninfected men. Factors implicated in semen alterations in HIV-1 patients were also analyzed. HIV-infected men (n=190), of whom 91% were undergoing antiretroviral therapy, and 218 fertile men were studied. Infertility risk factors were recorded and clinical examinations were performed for both groups. Records of history of HIV infection, antiretroviral treatment, and HIV-1 RNA detection in the blood as well as HIV-1 genome detection in the semen were obtained for the infected patients. Semen volumes, percentages of progressive motile spermatozoa, total sperm counts, and polymorphonuclear cell counts were decreased, while the pH values and spermatozoa multiple anomaly indices were increased in HIV-infected patients. Even after adjustment for possible sources of bias, the decreases in semen volume and progressive motility and the increase in pH remained significant. The present study demonstrates sperm motility and ejaculate volume alterations in HIV-1-infected patients, most of whom were receiving antiretroviral therapy. In HIV-1 patients, further longitudinal studies are required to analyze the impact of treatment regimen on sperm parameter alterations.

Ten-year variation in semen parameters and sperm deoxyribonucleic acid integrity in a healthy fertile man.

OBJECTIVE: To report parameters in semen samples and sperm DNA integrity in a healthy fertile volunteer over a 10-year period. DESIGN: Case report. SETTING: University-affiliated teaching hospital. INTERVENTION(S): None. PATIENT(S): Semen samples from a nonsmoking healthy male volunteer of proven fertility aged from 40 to 50 years were collected and analyzed over a decade. MAIN OUTCOME MEASURE(S): Semen parameters (sperm count, total sperm count, percentage of progressive motility grades a+b, morphology, and percentage of living spermatozoa) and sperm DNA integrity, measured by sperm chromatin structure assay (SCSA) and terminal uridine nick-end labeling (TUNEL) assay. RESULT(S): Median (min-max) value of total sperm count was 330 (126-511) million. Motility and vitality presented a median of 50% (40%-75%) and 78% (53%-92%), respectively. Among semen parameters, morphology and vitality showed the lowest within-subject coefficient of variation (CV(W)) and the total sperm count the highest (8.1% and 12.0% vs. 34.9%). Median values of DNA fragmentation index (DFI) and high DNA stainability (HDS) were 12.7% (7.9%-16.5%) and 6.5% (5.5%-8.2%), respectively. Sperm DNA fragmentation presented a median value of 8.9%, a minimum value of 1.4% and maximum value of 18.6%. Compared with TUNEL data, SCSA parameters (DFI and HDS) showed less variation over the data collection period (47.4% vs. 22.4% and 13.0%, respectively). CONCLUSION(S): Our data show that in this healthy fertile volunteer, semen parameters and sperm DNA integrity remained normal, and no trend was observed over the study period. More interestingly, in this subject aged from 40 to 50 years old, sperm nucleus status presented less than 20% of sperm DNA fragmentation over a decade.

Sublingual nitroglycerine as a tocolytic in external cephalic version: a comparative study.

OBJECTIVE: To study the effect of sublingual nitroglycerine as a tocolytic on the success rate of external cephalic version (ECV) in nulliparous and parous women. METHODS: A retrospective case-controlled study of all ECV cases from February 1996 to February 2000 in a single centre. The rates of successful ECV were compared between women who had their ECV before February 1998 (control group), those who had their ECV after February 1998 and received 0.8 mg sublingual nitroglycerine spray as a tocolytic agent, and those who had their ECV after February 1998 and received no tocolytic agents. Nulliparous and parous women were studied separately. Data were collected for parity, gestational age, maternal age, placental localization, and side effects. Chi-square and Kruskal-Wallis tests were performed for statistical comparison. RESULTS: Of 150 women who had their ECV after February 1998, 120 (80%) received sublingual nitroglycerine (group 1: cases using 0.8 mg sublingual nitroglycerine spray as a tocolytic agent) and were compared to the 30 patients who did not receive sublingual nitroglycerine or other tocolytics after February 1998 (group 2) and to 137 patients who had their ECV before February 1998 (control group). Of the women who received sublingual nitroglycerine, 5 (4%) had hypotension and 7 (6%) had headaches and/or nausea. The rate of successful ECV was 27% in group 1 versus 30% in group 2 (p = 0.86) versus 28% in the control group (p = 0.88) for nulliparous patients, and 67% versus 80% (p = 0.30) versus 51% (p = 0.09) respectively for parous women. However, the success rate was increased overall in parous women after the introduction of nitroglycerine as a tocolytic for ECV in February 1998 (71% vs. 51%, p = 0.02). CONCLUSION: Although the success rate of ECV has increased in recent years, the use of sublingual nitroglycerine as a tocolytic was not associated with this higher success rate. A randomized, controlled trial is needed.

A comparative study of manganese and lead levels in human umbilical cords and maternal blood from two urban centers exposed to different gasoline additives.

Manganese (Mn) and lead (Pb) are two neurotoxic chemicals and experimental evidence suggests that they can cross the placental barrier. Tetraethyl lead was still in use as an antiknock agent in Paris during the sampling period of the study, while it has been replaced by methylcyclopentadienyl manganese tricarbonyl (MMT) in Canada since 1977. By 1990, MMT was in 100% of gasoline in Canada. In a study of 160 pairs of mothers-neonates in Montreal and 206 pairs in Paris, we compared levels of Mn and Pb in the umbilical cord and in maternal blood. Neonates and mothers had significantly higher Pb levels in Paris where lead additives were still used in gasoline. Geometric mean maternal blood Pb levels were 5.4 microg/dl compared to 2.1 microg/dl in Montreal and cord blood Pb levels were 3.2 microg/dl in Parisian mothers compared to 1.7 microg/dl in Montreal. The prevalence of Paris Pb values superior to the 95th percentile of the Montreal distribution was highly elevated in all media studied. The prevalence of high Mn levels in umbilical cord blood was also significantly higher in Montreal. Surveillance programs are important to limit Pb overexposure and associated neurological effects in neonates where tetraethyl Pb is still in use as a gasoline additive. Since Mn is an essential element and dietary Mn intake may differ between Montreal and Paris, the difference observed with regard to high Mn values between Montreal and Paris cannot, at this time, be attributed to MMT in Montreal's gasoline. Further studies are needed to infer an association between Mn emissions from MMT and prenatal exposure to Mn.